tbuckley/cabot-search huggingface dataset:
Weight loss affects outcome in KrasG12C non-small cell lung cancer first line treated patients.
Authors: Sara Fancelli, Enrico Caliman, Serena Pillozzi, Brunella Napolitano, Edoardo Pieroni, Francesca Mazzoni, Luca Paglialunga, Marta Rita Gatta Michelet, Giandomenico Roviello, Francesca Castiglione, Caterina Bartoli, Lorenzo Antonuzzo
Journal: Journal of Clinical Oncology (2022)

e21054 Background: Cachexia is a syndrome characterized by weight loss (WL), reduction of muscle mass, systemic inflammation and is an independent criteria of worse clinical outcomes in cancer. Patients with KRASmut non-small cell lung cancer (NSCLC) experience a higher rate of WL than KRASwt patients. However no data about the prognostic value of each Kras mutation subtype for WL and/or BMI status are available. Methods: We reviewed the clinicopathological data of 110 NSCLC patients harboring KRAS G12 mutation who were treated at Clinical Oncology Unit, Careggi University Hospital in Florence, from March 2016 to March 2020. Patients received either chemotherapy or anti-PD1 pembrolizumab or a combination of chemo-immunotherapy as first-line treatment. The prognostic value of basal BMI and WL (&lt; and &gt; 5%) was analyzed according to each mutation subtype. Results: In the study population, 49.1% of patients harbor the KRAS G12C mutation, 20.9% G12V, 18.2% G12D and 11.2% of patients have other subtypes of KRAS mutations. Overall, our data confirm the better prognostic value of G12C mutation. At a median follow-up of 18 months, median OS for G12C patients was 17.5 months, longer compared to any other mutation subtype ( p = 0.113), whereas G12V mutation was associated with significantly worse outcomes than in the whole population (mOS 9.5 months IC 95% 6.0-17.0, p = 0.018). WL within 6 months of first-line therapy was observed in 29.7% and 35.3% of G12C and G12V-mutated patients, respectively. WL statistically decreased survival outcomes both in G12C (mPFS 4.0 months vs NR, p &lt; 0.001; mOS 12.0 months vs NR, p = 0.009) and in G12V patients (mPFS 3.0 months vs NR, p = 0.073; mOS 8.0 vs 12.0 months, p = 0.994), compared to patients who do not lose weight during treatment. Conclusions: WL significantly worsens clinical outcomes in G12C patients, with a similar trend in G12V. Further analyses in a larger population including a representative sample of less frequent mutations are needed.
Multi-omics analysis uncovers prognostic biomarkers and tumor ecosystem dynamics during sequential neoadjuvant treatment of dose-limiting chemotherapy combined with sintilimab for non-small cell lung cancer.
Authors: Bo Yang, Qi Song, Jie Li, Qi Xiong, Chaoyang Liang, Wenhao Zhou, Haitao Luo
Journal: Journal of Clinical Oncology (2022)

e20564 Background: Patients with non-small cell lung cancer (NSCLC) can benefit from the treatment of preoperative neoadjuvant chemotherapy combined with immunotherapy. However, the selection in concurrent or sequential neoadjuvant treatment is still controversial. Therefore, the effective form of sequential neoadjuvant treatment as well as predictive biomarkers are still need to be further investigated. Methods: We carried out a multi-omics study on 12 enrolled NSCLC patients who received sequential neoadjuvant and adjuvant treatments. The responses to therapy were rigorously evaluated. Biopsies pre and post neoadjuvant therapy were performed with whole-exome sequencing, transcriptome sequencing. Plasma at the different timepoints during therapy were collected and sequenced with TCR sequencing and ctDNA sequencing. Results: After neoadjuvant therapy, 10 were major pathological responses (MPR) and 2 were non major pathological responses (non-MPR). The analysis of TCR sequencing showed that high diversity along with the increase of dominance of T-cell receptor repertoire were observed after chemotherapy. At baseline, tumor mutational burden (TMB) and tumor neoantigen burden (TNB) were higher in MPR group when compared with non-MPR group. Furthermore, tumor infiltrating CD8+ naïve T cells, Tregs and monocytes were associated with clinical benefit and patients with high ratio of CD8+ naïve T cells and monocytes have better pathological response. Conclusions: In this study, sequential neoadjuvant treatment of dose-limiting chemotherapy combined with sintilimab showed a promising antitumor activity in patients with resectable NSCLC. The changes of genomic, transcriptome and TCR repertoire were comprehensively analyzed and correlated with clinical outcomes. TMB, TNB and TCR repertoire are associated with the clinical benefit. The sequential therapy would also impact the immune microenvironment. These result indicate that sequential neoadjuvant treatment of chemotherapy combined with immunotherapy could be a potential treatment for a defined group of patients with NSCLC.
Sweet-like syndrome and multiple COVID arm syndrome following COVID-19 vaccines: ‘specific’ patterns in a series of 192 patients
Authors: Anne-Sophie Darrigade, Bénédicte Oulès, Pierre Sohier, Marie-Laure Jullie, Philippe Moguelet, Annick Barbaud, Angèle Soria, Nicolas Vignier, Bénédicte Lebrun-Vignes, Paola Sanchez-Pena, Olivier Chosidow, Marie Beylot-Barry, Brigitte Milpied, Nicolas Dupin
Journal: British Journal of Dermatology (2022)

The two clinico-pathological patterns are 'Sweet-like syndrome' and 'Multiple COVID-Arm'. 'Sweet-like syndrome' presents clinically as erythematous and oedematous papules or plaques, sometimes developing vesiculation or bullae. Histology shows classical Sweet syndrome with a diffuse dermal neutrophilic infiltrate, or an infiltrate of histiocyte-like immature myeloid cells consistent with a histiocytoid Sweet syndrome. 'Multiple COVID-arm' is characterized by multiple large inflammatory plaques with histological analyses showing a perivascular and interstitial inflammatory infiltrate with eosinophils.
NFB-02. Maternal high-fat diet exposure increases the proliferation and glial differentiation of the cells of origin for NF1-optic glioma
Authors: Kailong Zhang, David Gutmann, Nicole Brossier
Journal: Neuro-Oncology (2022)

Abstract Some pediatric cancers arise in the context of tumor predisposition syndromes caused by germline mutations in genes that regulate cell growth. The most common of these syndromes, Neurofibromatosis type 1 (NF1), results in the development of low-grade tumors of the optic pathway (optic pathway gliomas; OPGs) in ~15% of affected children. However, risk assessment for each individual child is difficult, as it is currently challenging to predict which children with NF1 will develop OPG. Emerging human population-based evidence has raised the possibility that patient-specific risk factors, including infant birth weight, may modulate the risk of glioma development. High-infant birth weight can be modeled in mice by maternal exposure to a high-fat high-sucrose (HFHS) diet. To address the hypothesis that maternal high-fat diet exposure will increase the risk of OPG formation through intrinsic effects on the putative tumor cell of origin, we evaluated the effect of maternal exposure to a HFHS diet on the proliferation and differentiation of these cells (neural stem cells within the third ventricular zone; TVZ NSCs). Progeny from obese dams (MatOb) exposed to HFHS diet during and preceding gestation demonstrated increased proliferation and glial differentiation of TVZ NSCs in vivo. Similar results were observed with gestational HFHS diet exposure (GE) that did not result in maternal weight gain, suggesting these effects were related to maternal diet rather than weight. These effects were not observed in NSCs from other regions of the brain, supporting the regional specificity of the effect of diet on these tumor-initiating stem cells. Finally, we found that maternal HFHS diet resulted in elevated levels of leptin and insulin, both of which increase the proliferation of TVZ NSCs. Taken together, these findings provide early experimental evidence that maternal environmental exposure affects developing neural stem cells relevant to the risk of glioma formation.
Low doses of advanced glycation end-products and fructosilation products promotes premature cell death of human cardiac cells and increases drug resistance of human breast cancer cells exposed to doxorubicin through NLRP3 and MyD88 pathways.
Authors: Vincenzo Quagliariello, Martina Iovine, Giuseppe D'Aiuto, Simona Buccolo, Carlo Maurea, Annamaria Bonelli, Andrea Paccone, Maria Laura Canale, Nicola Maurea
Journal: Journal of Clinical Oncology (2022)

e24055 Background: Advanced glycosylation end-products (AGEs) are non-enzyme, protein glycosylation products caused by glucose-induced metabolic disorder, and play an important role in aging, cancer, metabolic syndrome and cardiovascular diseases. We aimed to assess whether AGEs and fructosilation products, such as methylglyoxal (MG) and N-carboxymethyllysine (N-CML) could increase susceptibility to cell damages induced by doxorubicin. Methods: Human cardiomyocytes were pre-exposed for 24h with low doses (50 mmol/L) of methylglyoxal (MG) or N-carboxymethyllysine (N-CML). After, cells were exposed to subclinical concentration of doxorubicin (at 100 and 200 nM) for 48 and 72h. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of peroxisome proliferator-activated receptor-α; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). Expression of p53 was also performed through western blot method. Results: Pre-exposure to methylglyoxal (MG) but especially to N-carboxymethyllysine (N-CML) increase cell mortality to doxorubicin of 48-53% compared to control. Pre-exposure to N-CML promotes premature death of cardiomyocytes to doxorubicin through NLRP3-driven pathways. Notably, MG and N-CML increased significantly the cardiotoxicity through NLRP3 inflammasome, Myd88 myddosome and cytochrome C-mediated apoptosis. Pre-exposure to N-CML and MG increase the secretion of interleukin-6 that increase cell apoptosis through a paracrine and autocrine mechanism. Induction of IL-6 reduces the expression of p53 resulting in the induction of the apoptotic process. Conclusions: These observations suggest that AGEs and fructosilation producs promotes premature cardiotoxicity of human cardiac cells exposed to doxorubicin by activation of NLRP3, Myd88-related pathways and downregulation of p53.
SWK-04. Investigation on Anxiety and Depression of Parents of Children with Central Nervous System Tumors
Authors: Huajun Yang, Yangqiong Zhang, Mingyao Lai, Juan Li, Linbo Cai
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE: Family members of children with Central Nervous System（CNS） tumors are often accompanied by anxiety, depression and other adverse emotions, which have a great impact on the quality of life of children. This study aims to investigate the incidence of anxiety and depression in parents of children with CNS tumors. METHODS: One of the parents of 165 children with CNS tumors who were hospitalized in Guangdong Sanjiu Brain Hospital from January 2021 to December 2021 were evaluated for anxiety and depression by SAS and SDS self-rating Depression Scale. The evaluation scores were compared with anxiety scores of normal Chinese population RESULTS: Our study cohort completed 165 questionnaires. Among them, 68 persons (41.21%, 68/165) had anxiety, and the anxiety score was (48.78±9.33), which was statistically significant compared with the normal Chinese population (29.78±10.01) (P &amp;lt; 0.01). 100 persons (60.61%, 100/165) had depression, and the depression score of the cohort was (55.02±9.98), higher than that of the normal population (33.46, 8.55), with statistical significance (P &amp;lt; 0.01). CONCLUSION: The parents of children with CNS tumor are the high risk group of anxiety and depression, which should arouse more clinical attention.
LGG-01. Children with Supratentorial Midline Pilocytic Astrocytomas Exhibit Multiple Progressions and Acquisition of Neurologic Deficits over Time
Authors: Nicole Brossier, Jennnifer Strahle, Samuel Cler, Michael Wallendorf, David Gutmann
Journal: Neuro-Oncology (2022)

Abstract Pilocytic astrocytomas are the most common solid tumor of childhood and can arise anywhere in the central nervous system, including the posterior fossa (pf-PA), supratentorial midline (sm-PA; including optic pathway, hypothalamus, thalamus), and brainstem (bs-PA). Location (sm, bs) has been previously proposed as a prognostic factor for PA, but is difficult to separate from resection status on multivariate analysis. To overcome this limitation, we assembled a large cohort of children (n = 251) with biopsy-proved PA treated at St. Louis Children’s Hospital from 2003 – 2021 and analyzed outcomes only in patients with subtotal resection (STR; n = 81). We excluded patients with NF1, as NF1-associated gliomas often display a more indolent clinical course than their counterparts. We identified that children with STR sm-PA had a higher likelihood of multiple progressions compared to children with STR bs-PA and pf-PA. This was associated with worsening neurologic deficits over time, consistent with the sm location as a poor prognostic factor. Furthermore, the only children in our cohort with leptomeningeal dissemination or death harbored sm-PAs. Tumors in this location were also associated with an increased likelihood of non-BRAF-fusion genetic alterations and multiple oncogenic mutations. Overall, these data support location as an independent prognostic factor for PA in cases in which a gross-total resection cannot be achieved. Treating neuro-oncologists may thus wish to consider early intervention rather than watch-and-wait strategies at first progression of STR sm-PA. These patients may also benefit from earlier consideration of molecularly targeted therapy.
Better (a little) late than never: The impact of steroidal treatment initiation timing on the outcome of patients with melanoma treated with immunotherapy.
Authors: Nethanel Asher, Neta Bar-Hai, Guy Ben-betzalel, Ronen Stoff, Shirly Grynberg, Jacob Schachter, Ronnie Shapira-Frommer
Journal: Journal of Clinical Oncology (2022)

9544 Background: The immune-system manipulation by immune-checkpoint inhibitors (ICI) has led to unprecedented clinical advances in melanoma. The management of the consequent immune-related adverse events (irAEs) is based mostly on steroids and other immune-modulators. Methods: A real world single-site cohort of metastatic melanoma patients who were treated with immunotherapy as first line between 2014 and 2020. This study explores the effect of dose, timing, and duration of steroid exposure on treatment efficacy. Results: Four hundred and forty patients were treated with either anti PD-1 (n = 285, 65%) or combination of anti PD-1 and ipilimumab ICI (n = 112, 25%), or ipilimumab alone (n = 43, 10%). The median age was 68 years [12-99y], and 57% were male. Any-grade irAEs were seen in 71% of the patients, and 49% were exposed to steroids. The median steroid dose was 0.75mg/kg prednisolone equivalent [0.03- 80mg/kg], the median duration of steroidal treatment was 11.2 weeks [0.1-316w] and the median time to onset of steroids was 7.6 weeks [0-193w]. Both experiencing irAEs, and the associated steroid exposure were associated with a significant progression free survival (PFS) benefit [HR 0.47, p &lt; 0.001; 95%CI 0.39-0.6 and HR 0.77, p = 0.026; 95%CI 0.60-0.97, respectively], regardless of dose and duration. Notably, within those who were exposed to steroids, an earlier onset of &lt; 4 weeks from immunotherapy initiation was significantly associated with a shorter PFS [HR = 3.5, p &lt; 0.001 (95%CI 2.32-5.45)]. This observation resulted significant also on multivariable analysis including other prognostic variables – ECOG PS, M-stage, LDH and protocol. Conclusions: Steroidal treatment during the immunotherapy priming phase (first 4 weeks) might have a deleterious effect on its’ efficacy and should be explored in larger prospective cohorts.
PROState pathway embedded comparative trial: An update to the IP3-PROSPECT study
Authors: E.J. Bass, N. Klimowska-Nassar, T. Sasikaran, E. Day, F. Fiorentino, M.R. Sydes, N. Arumainayagam, B. Khoubehi, T. Dudderidge, A. Pope, H. Sokhi, M. Winkler, H.U. Ahmed
Journal: European Urology (2022)
B cell depletion skews cd4+ t cell towards a pro-inflammatory phenotype in aged atherosclerotic mice
Authors: J De Mol, R Postel, V Smit, MNA Bernabe Kleijn, I Bot, J Kuiper, AC Foks
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation ERA CVD Aims Aging is associated with changes in the composition and function of the immune system, such as decreased B cell numbers and reduced antibody responses (1). In addition, aging is related to an increased incidence of inflammatory diseases, such as the lipid-driven chronic inflammatory disease atherosclerosis, the main underlying cause of cardiovascular disease (2). B cells play a major role in atherosclerosis progression by antibody secretion, antigen presentation and T cell regulation. Different B cell subsets, with either proatherogenic or antiatherogenic properties, have been identified in atherosclerosis, but the impact of aging on B cells during atherosclerosis remains to be elucidated. In contrast to young atherosclerotic mice where few B cells are found within the plaque, single cell RNA sequencing and flow cytometry data from our group revealed that B cells are one of the most dominant leukocytes present in atherosclerotic aortas from naturally aged LDLr-/- mice. In this study, we aimed to gain further insights into the role of these aged B cells on T cell immunity in atherosclerosis by depleting B cells in aged atherosclerotic mice. Methods and Results Aged (85-95 weeks) atherosclerotic male LDLr-/- mice were kept on a chow diet for six weeks, during which the mice received 250 µg B cell-depleting anti-CD20 antibody (Genentech) (n=12) or 250 µg rat IgG2a isotype control (n=12) once a week intraperitoneally. Mice that received the anti-CD20 antibody showed effective B cell depletion in the blood and lymphoid organs, such as the spleen and lymph nodes, but also locally in the atherosclerotic plaque. In addition, B cell depleted mice showed a significant increase in the percentage of T-bet expressing CD4+ T cells in aortic plaques compared to control mice (αCD20: 25.05±2.88% vs. ctrl: 15.94±2.14%, p&amp;lt;0.05). Furthermore, the percentage of RORyt+ and IL-17+ CD4+ T cells in the spleen and heart draining lymph nodes was increased after B cell depletion, indicating a shift towards Th17 differentiation. Conclusions Collectively, we show that CD20+ B cell depletion in aged LDLr-/- mice skews CD4+ T cells towards a Th1 phenotype in the atherosclerotic plaque and towards a Th17 phenotype in lymphoid organs, suggesting a protective role for aged B cells in atherosclerosis. However, B cells are a heterogeneous population and further research should elucidate whether aged B cells exert a pro- or anti-atherogenic role. In conclusion, our results indicate that aged B cells have an important function in CD4+ T cell differentiation and could be attractive targets to combat age-related cardiovascular disease.
US Food and Drug Administration Action on Menthol Cigarettes and Flavored Cigars—A Pivotal Moment for Health Equity
Authors: Andrea C. Villanti, Kymberle Sterling, Shyanika W. Rose
Journal: JAMA Network Open (2022)

In over a decade since the US Food and Drug Administration (FDA) gained regulatory authority over cigarettes, menthol cigarettes have eluded regulation.The most recent year of Federal Trade Commission cigarette sales data (2020) boasted the first increase in cigarette consumption in 20 years and the continued increase in menthol sales, comprising 37% of the cigarette market. 1 In addition to changes in the market, new evidence has continued to underscore the potential public health benefit of banning menthol cigarettes, including rigorous studies like that of Leas et al, 2 whose findings harness statistical methods designed to improve causal inference from observational studies.Like studies conducted in other cohorts, Leas et al 2 provide strong evidence that menthol cigarettes are associated with smoking uptake, progression to regular use, and nicotine dependence in youth.The magnitude of these findings, their consistency across samples and over time, and their coherence with the underlying physiological effects of menthol support that removing menthol from cigarettes is likely to benefit public health, especially as it relates to reducing youth smoking initiation.
CircSTX6 promotes pancreatic ductal adenocarcinoma progression by sponging miR-449b-5p and interacting with CUL2
Authors: Lingdong Meng, Yihan Zhang, Pengfei Wu, Danrui Li, Yichao Lu, Peng Shen, Taoyue Yang, Guodong Shi, Qun Chen, Hao Yuan, Wanli Ge, Yi Miao, Min Tu, Kuirong Jiang
Journal: Molecular Cancer (2022)

Abstract Background circular RNAs (circRNAs) have been reported to play crucial roles in the biology of different cancers. However, little is known about the function of circSTX6 (hsa_circ_0007905) in pancreatic ductal adenocarcinoma (PDAC). Methods circSTX6, a circRNA containing exons 4, 5, 6 and 7 of the STX6 gene, was identified by RNA sequencing and detected by quantitative reverse transcription PCR (qRT–PCR). The biological function of circSTX6 was assessed in vitro and in vivo. The relationship between circSTX6 and miR-449b-5p was confirmed by biotin-coupled circRNA capture, fluorescence in situ hybridization (FISH) and luciferase reporter assays. The interaction of circSTX6 with Cullin 2 (CUL2) was verified by RNA–protein RNA pull-down, RNA immunoprecipitation (RIP) and western blotting assays. Results circSTX6 was frequently upregulated in PDAC tissues, and circSTX6 overexpression promoted tumor proliferation and metastasis both in vitro and in vivo. Furthermore, circSTX6 expression was associated with tumor differentiation and N stage. Mechanistically, circSTX6 regulated the expression of non-muscle myosin heavy chain 9 (MYH9) by sponging miR-449b-5p. Moreover, circSTX6 was confirmed to participate in the ubiquitin-dependent degradation of hypoxia-inducible factor 1-alpha (HIF1A) by interacting with CUL2 and subsequently accelerating the transcription of MYH9. Conclusions Our findings indicate that circSTX6 facilitates proliferation and metastasis of PDAC cells by regulating the expression of MYH9 through the circSTX6/miR-449b-5p axis and circSTX6/CUL2/HIF1A signaling pathway. Therefore, circSTX6 could serve as a potential therapeutic target for the treatment of PDAC.
Renal function variation after nephroureterectomy for upper urinary tract carcinoma: Evaluation in a large multicenter cohort (Radical Nephroureterectomy Outcomes (RaNeO) Research Consortium)
Authors: A. Tafuri, M. Marchioni, C. Cerrato, A. Mari, A. Veccia, P. Parma, F. Dal Moro, R. Schiavina, P. Bove, F. Cantiello, F. Porpiglia, P. Ditonno, E. Montanari, P. Gontero, C. Trombetta, C. Terrone, L. Schips, A. Sciarra, A. Galosi, M. Ferro, S.F. Shariat, M. Di Nicola, A. Minervini, V. Pagliarulo, A. Antonelli
Journal: European Urology (2022)